The purpose of this project is to understand the role that proteoglycans play in the structure and function of tissues and during developmental events. We are characterizing tissues specific proteoglycans and determining the metabolic steps involved in their synthesis. Particular attention has been directed toward studying the heparan sulfate proteoglycan of basement membranes. We have identified the precursor protein which serves as a specific acceptor for the addition of heparan sulfate chains and established that several forms of the proteoglycan exist due to processing. Only one form, the largest, interacts strongly with other matrix components and the others may arise by degradation. We are also studying alterations in proteoglycan synthesis in human diseases such as diabetes and macular corneal dystrophy. In diabetes, there is a reduction in the synthesis of the basement membrane proteoglycan which produces basement membrane thickening due to compensatory hypertrophy. In macular corneal dystrophy, there is a failure to synthesize a mature corneal proteoglycan which results in corneal clouding and eventually blindness. We are also using mouse models to determine the mechanism by which teratogens disrupt the synthesis of the cartilage proteoglycan during chondrogenesis and of the basement membrane proteoglycan during myogenesis.